PT2045244E - Novel crystal of substituted phenylalkanoic acid and production process - Google Patents

Description

DESCRIPTION

" NEW REPLACED PHENYLCANOIC ACID CRYSTAL & PRODUCTION PROCESS "

Technical Field The present invention relates to novel crystals. More particularly, the invention relates to novel crystals of the compound 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, or a method of producing the crystals. Prior art

3- [3-Amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid has been reported to have a suppressing effect on the production of prostaglandins and a suppressing effect of leukotriene production and thus the usefulness of the compound in the prophylaxis and / or treatment of various inflammatory diseases caused by lipid mediators, autoimmune diseases, allergic diseases or pain, and methods of producing such compound are disclosed. 1 [Patent Type Document 1] WO 03/70686

Disclosure of the Invention

Problems to be Solved by the Invention It is an object of the invention to provide a preferred aspect or an improvement method when the compound of the present invention is used as a medicament.

Compound 1 of the present invention 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid (hereinafter can be referred to as " Compound 1 of the invention "), is obtained, according to the known production method described above, by adding a 2N aqueous solution of sodium hydroxide to a methanolic solution of 3- [3- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionate, stirring the solution of the mixture at 60 ° C for 16 hours, concentrating the reaction mixture under reduced pressure, acidifying the reaction mixture with 5% aqueous hydrochloric acid under ice-cooling, extracting the reaction mixture with ethyl acetate, washing the organic layer with brine, drying, and then drying. , distilling off the solvent under reduced pressure. According to this known production method, the compound of the invention is obtained as a colorless to brown oily matter. The inventor of the present invention understood that in administering Compound 1 of the invention as a medicament, further improvements were required to further facilitate handling. 2

Thus, we have investigated extensively and confirmed that Compound 1 of the invention is crystallized, thereby performing the present invention.

According to the present invention, once crystals of Compound 1 of the invention are provided, the handling in the formulation processes becomes easier, and it is easy to make the compound content of the invention constant in each preparation, which are extremely preferred . In addition, the crystals of the compounds of the invention also allow, by removing solvents and the like, easier and more complete removal of solvents and the like compared to the case of oily matter. Crystals are also suitable for industrial scale production and are most preferred.

In addition, the inventor of the present invention investigated the above-mentioned crystals and, as a consequence, determined that Compound 1 of the invention exists in the form of type A crystals and type B crystals, which are novel and exhibit the properties that will be described and that the crystals of the two types exhibit, respectively, preferred properties. The inventor has also established a method for selectively obtaining such crystals and has thus realized the present invention.

In addition, according to the known production method described above, 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] propionate (hereinafter referred to as " Compound 2 ") is obtained by adding an aqueous solution of 2M sodium carbonate, toluene and tetrakistriphenylphosphine palladium (0) to an ethanolic solution of 3- (3-bromo-4- hydroxy-5-nitrophenyl) propionate and 3-methyl-1H-indazole-5-boronic acid, stirring the solution of the mixture at 80 ° C for 16 hours, subsequently adding ethyl acetate to the reaction mixture, washing the reaction mixture sequentially with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and saturated aqueous sodium chloride solution, drying the organic layer, then distilling off the solvent under reduced pressure, and purifying the residue by column chromatography flash. With respect to this known production method, nothing is mentioned about the form of the compounds of the invention. According to this known production method, it can not necessarily be said that handling during production is easy. In addition, the inventor of the present invention has confirmed that in case Compound 2 is used as a medicament, problems occur in the production of a medicament with a constant content of the compound, easy removal of the solvent, and the like. The Applicant has also confirmed that Compound 2 can be obtained in a new crystalline form.

In addition, according to the known production method described above, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionate (hereinafter referred to as " Compound 3 ") is obtained by adding Raney 2800 nickel to a solution of Compound 2 described above in ethyl acetate / methanol, stirring the reaction mixture in an atmosphere of hydrogen at the temperature for 6 hours, subsequently filtering the reaction mixture, distilling off the solvent from the filtrate under reduced pressure and then purifying the residue by column chromatography. In this known production method, nothing is mentioned about the form of Compound 3, but it can not necessarily be said that handling is easy during production. In addition, the inventor of the present invention has confirmed that if Compound 3 is used as a medicament, problems occur in the production of a medicament with a constant content of the compound, easy removal of the solvent, and the like, and thus performed the present invention.

Thus, the present invention is as follows. (1) A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, wherein the crystal is a crystal 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid B having at least one or more characteristic peaks at 2Θ selected from 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation, or in that the crystal is a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid having at least one or more characteristic 2 p peaks selected from 6.9 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation.

In addition, the angle 2θ in the X-ray diffraction spectrum may have some admissible measurement error, due to various factors, and corresponding effective measurement values have fluctuations of generally ± 0.3 °, typically ± 0.2 °, and about ± 0.1 ° for more preferred measurements. Therefore, it is to be understood that in the present disclosure, angle 2Θ to 5 a specific sample obtained on the basis of effective measurement values may include such admissible error. (2) The crystal according to (1) above, wherein the crystal is a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H 5-yl) phenyl] propionic acid having characteristic peaks at 2Θ of 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 25.0 ± 0.2 ° and 27.5 ± 0.2 ° in an X-ray diffraction spectrum. (3) The crystal according to (1) or (2) above, wherein the crystal is a 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid type A crystal having an endothermic peak at about 182Â ° C in a differential scanning calorimetric analysis (heating rate: 10 ° C / min).

Furthermore, the endothermic peak in the differential scanning calorimetric analysis is an intrinsic property which is inherent to the crystals of the compounds of the invention, but it can not be denied that in the present measurement there is the possibility of a melting point fluctuation which may be attributed to the experimental error, as well as the incorporation of an optionally allowed amount of impurities and the like. Therefore, a person skilled in the art would understand sufficiently to what extent the actual endothermic peak temperature measurement values in the present invention can be varied, and for example, an error generally of about ± 5 °, typically about ± 3 ° and about ± 2 ° for preferred measurements. (4) The crystal according to any one of (1), (2) or (3) above, wherein the crystal is a type A crystal of 3- [3-amino-4- (indan-2- yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid having infrared absorption bands evident at wavelengths of about 3361, 2938, 1712, 1204, 1011 and 746 citT1 in a spectrum of absorption by the KBr disc method.

It should be noted that some error of measurement of the wave number in the infrared absorption spectrum is allowed, and it is considered that the present invention may also include this error. One of ordinary skill in the art would understand sufficiently the magnitude of the error and, for example, reporting to the 4th edition of the European Pharmacopoeia, it is pointed out that in an identification test using the infrared absorption spectrum, the data should be consistent at ± 0.5 % of the wave number scale when compared to the reference spectrum. According to the present invention, there is no particular limitation, but such a conventionally determined range of error can be considered and, for example as a measure, a change of about ± 0.8%, preferably about of ± 0.5% and particularly preferably about ± 0.2% for the effective measurement values on the wave number scale. (5) Type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of (1) to (4) above, wherein the crystalline purity is at least 90% by weight or greater. (6) The crystal according to (1) above, wherein the crystal is a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H -indazol-5-yl) phenyl] propionic acid having characteristic peaks at 2Θ of 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0, 2 and 22.9 ± 0.2 ° in an X-ray diffraction spectrum. (7) The crystal according to (1) or (6) above, wherein the crystal is a type B crystal of 3- [Indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid having an endothermic peak at about 203øC in differential scanning calorimetric analysis ( heating rate: 10 ° C / min). (8) The crystal according to (1), (6) or (7) above, wherein the crystal is a type B crystal of 3- [3-amino-4- (indan-2-yloxy) 5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid having infrared absorption bands evident at wavelengths of about 2939, 1720, 1224, 1016 and 751 æCi in an infrared absorption spectrum obtained by KBr disk method. (9) Type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any of (1) or (6) to (10) above, wherein the crystalline purity is at least 90% by weight or greater. (10) A pharmaceutical composition comprising any of a type A crystal or a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol- 5-yl) phenyl] propionic acid, as set forth in any of the above (1) to (9), as an active ingredient, and a pharmaceutically acceptable carrier. (11) The pharmaceutical composition according to (10) above, wherein the pharmaceutically acceptable carrier is a dry product and the pharmaceutical composition is a dry preparation. (12) A pharmaceutical composition comprising, as an active ingredient, a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5- yl) phenyl] propionic acid according to any one of (1) to (5) above, wherein the crystalline purity of the type A crystal is at least 90% by weight or greater and a pharmaceutically acceptable carrier. (13) A pharmaceutical composition comprising, as an active ingredient, a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5- yl) phenyl] propionic acid according to any one of (1) or (6) to (9) above, wherein the crystalline purity of type B crystal is at least 90% by weight or greater and a pharmaceutically acceptable carrier. (14) A method of producing a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of (1) to (5) above, the method comprising adding an acid to a basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl indan-5-yl) phenyl] propionic acid to afford crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl ] propionic acid and obtaining the crystals. (15) The method of producing a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid , according to (14) above, wherein the basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is an alkaline hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester. (16) A method of producing a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of (1) to (5) above, the method comprising adding an acid to the reaction solution obtained after an alkaline hydrolysis reaction of a 3- [3-amino-4- (indan- -2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, to thereby produce crystals of 3- [3-amino-4- (indan-2-yloxy) 5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and obtaining the crystals. (17) A method of producing a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of (1) or (6) to (9) above, the method comprising crystallizing 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl- indazol-5-yl) phenyl] propionic acid from a solution having 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid dissolved in any one or two or more solvents selected from the group consisting of acetone, dichloromethane, methanol, ethyl acetate, mixed solution of methanol / acetic acid and acetonitrile. (18) A method of producing a crystal according to any one of (1) or (6) to (9) above, the method comprising adding an acid to a basic solution of 3- [3-amino-4- - (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, thereafter adding B-type crystals of the compound as crystallization cores just before crystallization occurs by the addition of (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] acetic acid, propionic acid. (19) The method of producing a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid , according to (18) above, wherein the basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is an alkaline hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester. (20) A method of producing a crystal according to any one of (1) or (6) to (9) above, the method comprising adding an acid to the reaction solution obtained after an alkaline hydrolysis reaction of an alkyl ester 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, thereafter adding B-type crystals of the compound as nuclei of crystallization to the reaction solution immediately before crystallization occurs by addition of the acid, whereby type B crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1 methyl-1H-indazol-5-yl) phenyl] propionic acid.

The crystals of Compound 1 of the invention are very advantageous in the formulation processes, insofar as it is easy to make the content of the compound of the invention constant in each preparation, and the like. In addition, the crystals are also favorable in that it is easy to remove the solvents and the like from them, in comparison with the case of the oily matter, and are thus suitable for production on an industrial scale. 11

As the crystals of Compound 1 of the invention used in certain aspects of the present invention, type A crystals may be favorably mentioned. The type A crystal of Compound 1 of the invention is a crystal defined by any one or two or more combinations of the various properties described in the above-mentioned inventions (1) to (5) or various properties confirmed in the Examples, Test Examples and the like of the present disclosure. From the fact that this type A crystal exhibits certain properties, in addition to the advantages held by the crystals of Compound 1 of the invention described above, it has been confirmed that type A crystal exhibits preferred properties as a preparation or in the manifestation of the pharmacological action and in the production processes, by comparison with the uncontrolled single crystals. In addition, it is recognized that the type A crystal described above has a higher solubility in aqueous solvents, for example, compared to the type B crystal which will be described later and is therefore preferred in this regard.

In order for the preferred effects held by the type A crystal to manifest at its maximum, it is preferred to use crystals which are substantially type A crystals and as such form of the type A crystals, type A crystals having a crystalline purity (in percent) which is generally about 90% by weight or greater, and crystals having a crystalline purity of preferably 95% by weight or greater, more preferably 97% by weight or greater may be mentioned , even more preferably 99% by weight or greater, and particularly preferably about 100% by weight. Also, in some cases a crystalline purity of 93% by weight or greater is preferred, more preferred is that of 98% by weight or greater and particularly preferred is that of 99.5% by weight or greater. In addition, in the case of using the crystals as a medicament of the invention, a crystalline purity of 80% by weight or greater may also generally be favorable. In addition, as a preferred aspect of type A crystals there may be mentioned those crystals not essentially containing any type of crystal other than type A. The term " not essentially containing " means that the crystals contain any other types of crystals other than the type A crystal, preferably in an amount of 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, and particularly preferably 1% by weight or less, and most preferably do not contain any other types of crystals at all.

As the crystals used in another aspect of the present invention, type B crystal may also be mentioned as a preferred example. The type B crystal of Compound 1 of the invention is a crystal defined by any one or two or more combinations of various properties described in the above-mentioned inventions (1) or (6) to (9), or various properties confirmed in the Examples, Examples of Assay and the like of the present disclosure. From the fact that this type B crystal exhibits certain properties, in addition to the advantages held by the crystals of Compound 1 of the invention described above, it has been confirmed that type B crystal exhibits preferred properties as a preparation or in the manifestation of the pharmacological action , and in the production processes compared to single, uncontrolled crystals. Furthermore, this type B crystal has higher filterability compared to type A crystal and, in addition, has improved flow properties, and thus, for example, in the case of mass production of Type B crystals, it is expected that the time spent in the filtration process and / or the dehydration process can be shortened. In addition, type B crystal is most preferred in the case of the production of dry preparations or solid preparations. It has been confirmed that type B crystal after filtration and dehydration has a water content lower than type A crystal after filtration and dehydration, and thus is expected to be and is considered to be preferred, particularly in the case of production by mass, to reduce the time spent in drying or reduce heating energy. Furthermore, it is thought that this type B crystal has a substantially more favorable morphological stability than type A crystal. In order to maximize the effects held by the type B crystal, it is preferred to use crystals which are essentially type crystals B, and such type B crystals may be mentioned type B crystals having a crystalline purity (in percent) which is generally about 90% by weight or greater, and those crystals having a crystalline purity preferably 95% by weight or greater, more preferably 97% by weight or greater, even more preferably 99% by weight or greater, and particularly preferably about 100% by weight. Also, in some cases, a crystalline purity of 93% by weight or greater is preferred, more preferred is that of 98% by weight or greater, and particularly preferred is that of 99.5% by weight or greater. In addition, in case the crystals are used as a medicament of the invention, a crystalline purity of 80% by weight or greater may also generally be favorable. Furthermore, as a preferred aspect of type B crystals there may be mentioned those crystals not essentially containing any other type of crystal other than type B. The term " not essentially containing " means that the crystals contain any other types of crystals 14 different from the type B crystal, preferably in an amount of 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, and particularly preferably 1% by weight or less, and most preferably do not contain any other types of crystals at all.

In addition, crystalline purity (in percent) of the type A crystal can be calculated by dividing the weight of the type A crystals by the total weight of the Compound 1 of the invention containing the type A crystals, and multiplying the result by 100. Here, as the method for measuring the weight of type A crystals, or the weight of the presence of Compound 1 of the invention, any of the following methods may be applied, which may be further modified as appropriate.

In addition, there may be cases where measurement errors appear in excess of what is required, depending on the measurement method, but in this case, it is preferable to check the error size using standard materials of known quantities and correct the error. For example, according to the present invention, it is particularly preferred to indicate crystalline purity using a value which is calculated by dividing the measured value for the crystal obtained by measurement using differential scanning calorimetric analysis (in particular, the specific measurement conditions described in the present description may be mentioned as particularly preferred examples) by the measured value for Compound 1 of the invention obtained by measurement by means of HPLC (in particular, the specific measurement conditions described in the present description may be mentioned as particularly preferred examples) and multiplying the result by 100. In addition, the same method 15 as described above may also be applied to determining the crystalline purity (in percent) of the type B crystal, although appropriate modifications may be made to the measurement methods. Specifically, it is particularly preferred to indicate crystalline purity using a value that is calculated by dividing the measured value for the crystal obtained by the measurement using differential scanning calorimetric analysis (in particular, the specific measurement conditions described in the present description may be mentioned as particularly preferred examples) by the measured value for Compound 1 of the invention obtained by measurement by means of HPLC (in particular, the specific measurement conditions described in the present description may be mentioned as particularly preferred examples), and by multiplying the result per 100.

In summary, the amount of each crystal can be calculated by measuring the characteristic peak intensities in differential scanning calorimetric analysis, X-ray diffraction spectrum, infrared absorption spectrum, 13 C solid NMR spectrum, Raman spectrum and and in particular in the case of measuring the presence ratio between the type A crystal and the type B crystal of Compound 1 of the invention as described above, there may be mentioned the method of measuring the amounts by scanning calorimetric analysis as a preferred example. In a specific method for determining the amount of the type A crystal of Compound 1 of the invention using a differential scanning calorimetric analysis using a suitable heating rate (as the suitable heating rate can be mentioned, for example, 50 ° C / min) pure type A crystals are used as the standard crystalline material and a calibration curve is plotted graphically representing the weight (mg) of the standard material against the endothermic peak area (mJ) of about 185øC, which indicates the fusion of the type A crystals. Thereafter, the endothermic peak area (mJ) of about 185øC measured for the sample is compared with the calibration curve described above. Thereafter, the amount of the type A crystal can be calculated. Similarly, for the type B crystal of Compound 1 of the invention, the amount can be calculated in the same manner. That is, for example, using pure type B crystals as the standard crystalline material, the near endothermic peak area of about 205Â ° C can generally be measured as the endothermic peak for type B crystal in differential scanning calorimetric analysis .

Also in measurement methods other than differential scanning calorimetric analysis, namely measurement methods such as X-ray diffraction spectrum, infrared absorption spectrum, 13 C solid NMR spectrum and Raman spectrum, the amount of the crystals of the desired type can be calculated by preparing a calibration curve in the same manner as in differential scanning calorimetric analysis using a material standard.

In particular, in the case of determining the amount of crystals of the desired type by a measuring method other than differential scanning calorimetric analysis, namely, X-ray diffraction spectrum, infrared absorption spectrum, 13 C NMR spectrum of solids, Raman spectrum or the like, a calibration curve can be prepared by suitably selecting peaks which are characteristic of the respective crystalline types and the amount of presence of the crystals of the desired type can be calculated. 17

In addition, as the optical system used in X-ray diffraction spectrometric measurement, an optical system for the general focusing method, or an optical system for the parallel beam method, may be exemplified. The optical system to be used is not particularly limited, but when it is desired to guarantee resolution or intensity, it is preferred to carry out the measurement using an optical system for the focusing method. Furthermore, when it is desired to suppress the orientation, which is a phenomenon in which the crystals are oriented in a certain direction due to the crystalline form (needle shape, plate shape, etc.), it is preferable to carry out the measurement using a for the parallel beam method. As the metering apparatus for the optical system for the focusing method may be mentioned XRD-6000 (SHIMADZU CORPORATION), MultiFlex (Rigaku Corporation) and the like. In addition, as the measuring apparatus for the optical system for the parallel beam method may be mentioned XRD-7700 (SHIMADZU CORPORATION), RINT2200Ultima + / PC (Rigaku Corporation) and the like.

When it is necessary to measure the amount of Compound 1 of the invention in a preparation, it is generally convenient and preferable to use HPLC. Specifically, for example, a calibration curve is prepared by performing HPLC measurements using a standard material of Compound 1 of the invention with known purity and the amount of Compound 1 of the invention in the sample can be quantified based on this calibration curve. The HPLC quantification method and the crystal measurement method with respect to Compound 1 of the invention as described above are applicable in a manner similar to Compound 2 or Compound 3, which will be described below. For example, with respect to HPLC conditions, it is possible to carry out the measurements under the same conditions as described above and also for the method of measurement by means of differential scanning calorimetric analysis, the measurement can be made using characteristic endothermic peaks for the respective compounds. In addition, the respective crystalline purity may also be calculated in the same manner as described above. Type A crystals and pure Type B crystals of Compound 1 of the invention to be used as standard material in the measurement described above as well as the pure Type A and Type B crystals of Compound 1 of the invention to be used as crystallization cores used in the method of crystal production which will be described later, may respectively be obtained according to the respective methods described in Examples 3, 4 and 5, and thereafter by particularly selecting crystals from among those, and further selecting the crystals which exhibit a single characteristic endothermic peak by differential scanning calorimetric analysis. Type B crystals obtained according to the respective methods of Examples 6 and 7 can also be used as the standard material. It is also possible to use the type B crystals obtained according to the respective methods of Examples 6 and 7 as crystallization cores to obtain pure type B crystals. By the way, if type A crystals are contaminated with type B crystals there are cases where the quantified value of type A crystals obtained by differential scanning calorimetric analysis can be underestimated compared to the quantified value of type A crystals from authentic standard material. The size of the error in this case may vary depending on the proportion of contamination of type B crystals in type A crystals, but if, for example, the contamination ratio of type B crystals is within 10%, there is generally a possibility of an error of about 10% may be observed in the quantified value for the type A crystals. Likewise, if the contamination ratio of type B crystals is almost 50%, there is a possibility of an error of up to about 20% maximum. In contrast, if type B crystals are contaminated with type A crystals, there are cases where the quantified value of type B crystals can be overestimated compared to the quantified value of type B crystals of an authentic standard material. Although in this case the error size may also vary depending on the proportion of contamination of type A crystals relative to type B crystals, for example if the proportion of contamination of type A crystals is almost 10%, there is generally possibility of an error of about 10% in the quantified value of type B crystals. Likewise, if the proportion of the type A crystal contamination is almost 50%, there is a possibility of an error of up to about 20% maximum. In particular, even in a normal state where the proportion of contamination relative to each other is not so high, the calculated crystalline purity for type A crystals or type B crystals may include an error of about 10% . Therefore, quantification may be accomplished by preparing a calibration curve using a standard material having an expected contamination ratio. In addition, to determine the proportion of contamination with greater accuracy, a series of mixtures of the standard type A crystal and the standard type B crystal with predetermined mixing ratios are prepared and a calibration curve is produced to show the relationship between the proportions (percentage) of the mixed crystals and the area of each endothermic peak (mJ) corresponding to the melting of each crystal as a percentage based on the total area of the peaks. Then, the proportion of contamination in the test product can be evaluated from this calibration curve. 20

With respect to measurement methods other than differential scanning calorimetric analysis, namely, measurement methods such as X-ray diffraction spectrum, infrared absorption spectrum, 13 C solid NMR spectrum and Raman spectrum, also it is possible to determine the proportion of contamination more accurately from a calibration curve produced using a series of mixtures of standard materials with predetermined mixing ratios.

Best Mode for Carrying Out the Invention [Method of producing Type A crystals of Compound 1 of the Invention]

As the production method of the type A crystals of Compound 1 of the invention, there may be mentioned a method of adding an acid to a basic solution of Compound 1 of the invention to produce crystals of Compound 1 of the invention and thereby obtaining the crystals.

That is, the basic solution of Compound 1 of the invention as used in the present invention is not particularly limited so long as it is a solution having the compound dissolved under basic conditions and, here, the compound to be dissolved may be in any of an oily state , solid state (including various crystalline types and amorphous type), and mixtures thereof. Compound 1 of the invention may be prepared according to the method described in International Patent Publication No. WO 03/70686. 21

Inorganic bases are preferred as the base used to prepare the basic solution as described above. That is, for example, alkali metal bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide and potassium t-butoxide, and the like may be mentioned. Sodium hydroxide, potassium hydroxide and the like are preferred, and sodium hydroxide may be mentioned as a particularly preferred example. These bases may be used in the form of a solution prepared by dissolving them in water or an alcohol, such as methanol, ethanol or t-butanol. It is particularly preferred to prepare and use an aqueous solution containing a base at a predetermined concentration insofar as it is easy to define the amount of an acid to be added, and the like. However, in the case where a concentrated basic solution is used, there is a concern that when later an acid is added, high heating occurs due to the neutralization reaction and thus the use of a 0.5 base aqueous solution to 2 N may be mentioned as a most preferred example. The amount of base to be added may be, as a lower limit, generally 0.8 equivalents or more, preferably 0.9 equivalents or more, and more preferably 1.0 equivalent or more, relative to 1 equivalent of the compound . As the upper limit, generally 3.0 equivalents or less may be mentioned with respect to 1 equivalent of the compound, and 2.0 equivalents or less may be mentioned as a preferred example. 22

As the solvent to be used to dissolve the compound together with the base, polar solvents may be mentioned, and specifically water, alcohols, such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetone and the like. Mixtures thereof may also be used as required. Among those preferred are water, methanol, ethanol, tetrahydrofuran and the like, and water, methanol, ethanol and the like are particularly preferred. In addition, it is most preferred to use a mixture of water and methanol, and the proportion of the mixture of water-methanol to be obtained after preparation of the solution containing a base, may be, for example, 1:20 to 10: 1, while it is preferred a ratio of 1:10 to 1: 1. The basic solution described above may be heated to a temperature less than or equal to the boiling point of the solvent and, if insoluble materials are present, it is preferred to remove the insoluble materials by processes such as filtration.

As the acid to be added to the solution described above, the acid may be in any liquid state, solid state and gaseous state, as long as the acid is not incorporated into the precipitate of crystals produced upon addition of the acid. However, the acid is preferably in a solution state or gaseous state, while an acid in the solution state may be mentioned as a preferred example.

In addition, the type of acid may be any of the organic acids and inorganic acids. However, since the acid to be used should neutralize the base, it is necessary that the acidity of the acid is higher than the acidity of the compounds of the invention. Thus, mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid are preferred and hydrochloric acid is particularly preferred. These may also be used in the form of a solution prepared by dissolving them in water or an alcohol, such as methanol, ethanol or t-butanol. It is preferred to prepare and use an aqueous solution containing an acid at a predetermined concentration, insofar as it is easy to define the amount of solution to be added, and the like. However, in the case where a concentrated acid solution is used, there is a concern that high heating occurs due to the neutralization reaction, and thus the use of an aqueous solution of 0.5 to 2 N acid can be mentioned as a particularly preferred example.

As the amount of acid to be added, the acid may be added to the extent that sufficient crystals are produced and, therefore, the amount is not particularly limited. However, for example, 0.8 equivalents or more may be mentioned in relation to 1 equivalent of base and it is preferable to add 0.9 equivalents or more. Also, it is particularly preferable to add about 1 equivalent. In addition, there is no particular limitation with respect to the upper limit, but, for example, 1.5 equivalents or less, and preferably 1.2 equivalents or less relative to 1 equivalent of base, can generally be mentioned. The acid addition method may be exemplified by (1) addition of a single once, (2) addition in several divided portions, (3) continuous addition over a time period by dropwise addition, or the like, but a continuous addition method over a period of time is preferred by a method such as dropwise addition. When adding an acid, stirring is preferred. The rate of addition may vary depending on the amount of the compound used, the concentration of the base in the basic solution, the type of acid used or the concentration of the acid solution. However, if 0.5 to 2 N hydrochloric acid is used, a method of adding the entire amount may be mentioned over 1 hour to 6 hours.

As regards the addition temperature of the acid, the upper limit is preferably 60 ° C or less, more preferably 50 ° C or less, and even more preferably 45 ° C or less, while that the lower limit is preferably 0 ° C or more, more preferably 10 ° C or more, and even more preferably 25 ° C or more. The production of the produced crystals can generally be carried out within 24 hours, preferably within 20 hours, and particularly preferably within 10 hours, after addition of acid. The crystals can also be collected immediately after addition of the acid, but it is preferred to collect the crystals after 1 hour of the addition of acid, and particularly preferably after 3 hours of acid addition.

As the method for collecting precipitated crystals, it is possible to obtain crystals by a known method, such as filtration or decantation, but filtration is generally preferred. In addition, after collecting the crystals by filtration, the crystals can be washed with a polar solvent, for example water, methanol, ethanol or a mixed solution thereof, and this process is effective as a process to remove impurities. As the washing method 25, a method of washing the crystals in the filtration vessel with a polar solvent is preferred. It is also preferable to use a method of introducing the crystals into a polar solvent, such as water, methanol, ethanol or a mixture thereof to form a suspension, sufficiently stir the suspension and then filter the crystals again to obtain crystals. In addition, it is particularly preferable to carry out both the above described washing processes. The collected crystals may be dried by a generally performed drying method, such as drying under reduced pressure, drying under reduced pressure while heating, drying under normal pressure while heating, or air drying. The final concentration of the compound after adding the acid to the basic solution to complete the precipitation may vary depending on the type of solvent used and, in the case of a solvent mixture, may also depend on the mixing ratio. However, the lower limit may be generally 1% w / v or more, and preferably 5% w / v or more. For example, the upper limit may be preferably 30% w / v or less and more preferably 20% w / v or less.

In addition, in producing crystals, the addition of a small amount of type A crystals as crystallization cores is considered to be a preferred embodiment.

As a preferred example among the production methods described above, the following may be mentioned. In the three examples of the following production methods, the preferred examples described above can be used for the amount of base used, the stirring temperature before the acid addition, the amount of acid added and the stirring time after addition of acid .

A method of adding continuously over time to a solution containing 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and 0.8 to 3.0 equivalents of sodium hydroxide or potassium hydroxide relative to the amount of said compound in water, methanol, ethanol, tetrahydrofuran or a solvent mixture thereof, 0.8 to 1.5 equivalents of a aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid relative to 1 equivalent of said base by a method such as adding dropwise at a temperature of 10 to 50 ° C under stirring; and stirring further for 1 to 24 hours to obtain crystals.

A method of adding over 1 hour to 6 hours to a solution containing the above compound and 0.9 to 2.0 equivalents of sodium hydroxide relative to 1 equivalent of said compound in water, methanol, ethanol or a mixture thereof solvent, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution to 1 equivalent of said base, at a temperature of 25 to 45 ° C under stirring; and stirring further for 3 to 24 hours to obtain crystals.

A method of adding over 1 hour to 6 hours to a solution of the above compound in a mixture of methanol and a 0.5 to 2 N aqueous sodium hydroxide solution in an amount to give 0.9 to 2.0 equivalents of with respect to 1 equivalent of said compound, a 0.5 to 2 N aqueous hydrochloric acid solution in an amount corresponding to 0.9 to 1.2 equivalents relative to 1 equivalent of said base at a temperature 27 of 25 to 45 ° C under stirring; and stirring further for 3 to 24 hours to obtain crystals.

In addition, the basic solution of Compound 1 of the invention may be an alkaline hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H- indazol-5-yl) phenyl] propionic acid. That is, as another method of producing type A crystals, the following may be mentioned.

A method of subjecting a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester to alkaline hydrolysis in solvent and then addition of an acid to said hydrolyzate solution which is under basic conditions to obtain crystals. 0 " lower alkyl ester " includes a carboxylic acid ester of an alkyl group having 1 to 4 carbon atoms and the alkyl group having 1 to 4 carbon atoms may be any of a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a t-butyl group. Among those, a methyl group and an ethyl group are particularly preferred examples. The 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester can be prepared according to method of International Patent Publication No. WO 03/70686.

As the base used in the preparation of the alkaline hydrolyzate of the compound described above, the bases used to prepare the basic solution described above may be used. The amount of base used may generally be exemplified by 1 equivalent or more relative to 1 equivalent of the compound. As the upper limit, 10 equivalents or less may generally be mentioned with respect to 1 equivalent of the compound, and there may for example be mentioned 3 equivalents or less, and particularly preferably 2 equivalents or less.

As the solvent, it is generally preferred an inert solvent that does not interfere with the reaction, and preferably a solvent among the polar solvents, which allows the reaction to take place. Although reference may be made to the conditions described above, the polar solvent may be exemplified by water, methanol, ethanol, tetrahydrofuran, dioxane and the like, and if necessary, they may be mixed and used. Among these, water, methanol, ethanol, tetrahydrofuran and the like are preferred, and water, methanol, ethanol and the like are particularly preferred. In addition, it is most preferred to mix water and methanol for use, and after adding the base, the mixing ratio of water-methanol in the reaction solution may be 1:20 to 10: 1, a ratio of 1:10 to 1 being preferred :1.

In addition, for the reaction temperature of the alkaline hydrolyzate, a suitable temperature may be selected, for example, from room temperature to reflux temperature, and particularly preferably a condition of 50 to 70øC. The reaction time can generally be exemplified by 0.5 to 72 hours, and preferably 1 to 24 hours. More specifically, as the upper limit 24 hours or less are preferred, 20 hours or less are more preferred, and 10 hours or less are still more preferred. As the lower limit, 29 0.5 hours or more are preferred, 1 hour or more is preferred, and 3 hours or more are still more preferred. However, since the progress of the reaction can be monitored by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) or the like, the reaction can generally be appropriately completed when the yield of 3- [ The obtained 3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is most effective.

After the alkaline hydrolysis reaction, the acid to be added to the solution under basic conditions, the conditions for producing crystals, the method of collection, and the like are as described above.

Among the production methods described above, a preferred example may be as follows. For the three examples of the following production methods, the preferred examples described above may be used with respect to the amount of base used for the alkaline hydrolysis, the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before addition of acid, amount of acid to be added and time of stirring after addition of acid.

A method for allowing a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester to react in water, methanol, ethanol, tetrahydrofuran or a solvent mixture thereof in the presence of 1 to 3 equivalents of sodium hydroxide or potassium hydroxide relative to 1 equivalent of the lower alkyl ester at 50 to 70 ° C for 1 to 24 hours; then continuously adding to the temperature at a temperature of from 10 to 50 ° C under stirring, 0.8 to 1.5 equivalents of an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid relative to 1 equivalent of the base by a method such as dropwise addition; and then stirring for 1 to 24 hours to obtain the crystals.

A method for allowing a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid methyl or ethyl ester to react in water , methanol, ethanol or a solvent mixture thereof in the presence of 1 to 2 equivalents of sodium hydroxide relative to 1 equivalent of the methyl or ethyl ester at 50 to 70 ° C for 1 to 24 hours; then add 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution over the base over 1 hour to 6 hours at 25-45 ° C under stirring; and then stir for 3 to 24 hours to obtain the crystals.

A method of adding 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-

yl) phenyl] propionic acid, a mixture of methanol and 1 to 2 equivalents of a 0.5 to 2 N aqueous sodium hydroxide solution to 1 equivalent of the methyl or ethyl ester, allowing the mixture to react at 50 to 70 ° C for 1 to 24 hours; then add, for 1 hour to 6 hours, at 25-45 ° C under stirring, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution to 1 equivalent of base; and then stir for 3 to 24 hours to obtain the crystals. 31 [Method of producing Type B crystals of Compound 1 of the invention]

As the B-type production method of the Compound of the invention, there may be mentioned a method of crystallizing Compound 1 of the invention from a solution having the compound dissolved in any one or two or more solvents selected from the group consisting of acetone, dichloromethane, methanol, ethyl acetate, a mixed solution of methanol / acetic acid and acetonitrile. Compound 1 of the invention may be prepared according to the method described in International Patent Publication No. WO 03/70686 or the like, as described above.

Further, as the solvent to be used above, acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, nitrobenzene, 2,2,2-trifluoroethanol, N, N-dimethylformamide, N , N-dimethylacetamide and the like, and these solvents may also be mixed and used. Further, there may be mentioned tetrahydrofuran / water, N, N-dimethylformamide / water, N, N-dimethylacetamide / water, tetrahydrofuran / methanol, diisopropyl ether / acetic acid, methanol / acetic acid and the like. Among these, acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, methanol / acetic acid and the like are preferred, and acetone, dichloromethane and the like are particularly preferred. 32

After dissolving the compound in a solvent, it is preferred to heat the solution to a temperature less than or equal to the boiling point of the solvent, from the standpoint of the yield obtainable for the resulting crystals, and the like, and if insoluble materials are present , the insoluble materials can be removed by processes such as filtration. The amount of solvent to be added may vary depending on the type of solvent used, and in the case of a mixture of solvents, the mixing ratio. However, it is preferred to use the solvent in an amount that dissolves the compound at a temperature equal to or less than the boiling point of the solvent used, and it is particularly preferable to use an amount that dissolves the compound near the boiling point of the solvent to the concentration of saturation, from the standpoint of yield which can be obtained for the resulting crystals. Specifically, for example, if acetone is used as the solvent, 15 to 25 ml are preferred based on 1 g of the compound and about 15 ml may be mentioned as a more preferred example. Also, if dichloromethane is used, for example, it is preferred to use an amount of 30 to 50 ml based on 1 g of the compound and about 30 ml may be mentioned as a more preferred example.

As the cooling method of the solution of the compound prepared with heating, methods such as rapid cooling, gradual cooling, allowing the solution to cool itself naturally, and the like can be mentioned. However, a gradual cooling method or a method which allows the solution to cool naturally is preferred. The degree of cooling may vary depending upon the amount of solvent used, the type of solvent used and, in the case of a mixture of solvents, the mixing ratio, and may vary depending on the temperature during the dissolution process of the compound. However, it is preferred to cool the lower solution to a temperature at which the saturation concentration of the compound is reached. The cooling step may be carried out under stirring or may be performed while standing. However, it is preferred to carry out the cooling under agitation in that it accelerates the precipitation of crystals and shortens the operating time.

In addition, by producing crystals by the method described above, the addition of a small amount of type B crystals as crystallization cores is also a preferred aspect. Harvesting the precipitated crystals can generally be accomplished by filtration. In addition, after collection of the crystals by filtration, the crystals may be washed with a solvent used in the dissolution of the compound or a solvent which does not significantly dissolve the crystals, or a mixed solution thereof. This step is effective in removing impurities.

The collected crystals may be dried by a generally accomplished drying method, such as drying under reduced pressure, drying under reduced pressure while heating, drying under normal pressure while heating, or drying in the air.

A preferred example of the above production method may be exemplified by the following. 34

A method of adding a portion of 15 to 25 mL of acetone or a 30 to 50 mL portion of dichloromethane to 1 g of Compound 1 of the invention, heating the mixture to a temperature near the boiling point of the solvent to dissolve the compound , filtration of insoluble materials as required; subsequently stirring at room temperature for several hours to several days; and then obtaining the crystals generated.

As another production method with respect to the type B crystals of Compound 1 of the invention, a method of adding B-type crystals of Compound 1 of the invention as crystallization cores may be mentioned during the process of adding an acid to a basic solution of Compound 1 of the invention but just before Compound 1 of the invention begins to crystallize, thereby allowing Compound 1 of the invention to crystallize as Type B crystal, and to obtain the crystals. Compound 1 of the invention used in the present invention, its form and the method of obtaining the compound are the same as those described in the description in the " A-type crystal production method of Compound 1 of the invention. &Quot; In addition, the same method as described above can be used to prepare a basic solution of Compound 1 of the invention. It is also as described above that the basic solution may be an alkaline hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5 -yl) phenyl] propionic acid.

Moreover, the same as described above may also apply to the type, amount of addition or the like of the base used to prepare the basic solution; to the type, amount of addition or the like of the solvent used for dissolving the compound together with the base; and the type or amount of addition of the acid to be added, the method of addition, rate of addition, temperature during addition and the like. With regard to the method of adding the crystallization nuclei of type B crystals, it is preferred that no crystal is present in the solution of the mixture when the crystallization cores are added, and it is preferred that the added crystallization cores do not dissolve in the solution. In the case of the addition of an acid to the solution of the compound prepared by adding thereto a base in an amount equal to or excessive to the amount of the compound, it is preferable to add the crystallization nuclei of the type B crystals when the excess base is neutralized by the acid added to avoid dissolution of the crystallization nuclei. In addition, at that time, it is also a preferred method to confirm the neutralization of the excess base, using an instrument such as a pH meter. That is, for example, if the compound was dissolved using 1.5 equivalents of base relative to the compound, it may be mentioned as a preferred example that the crystallization cores can be introduced after the pH of the solution shows poor basicity, g. to about pH 7 to 9 by the addition of an acid in an amount equivalent to 0.5 equivalents. It is also preferable to add the crystallization cores before crystals are generated upon addition of acid. When 2N hydrochloric acid is added over 1 hour to 6 hours, since crystallization is most likely to occur when the pH of the solution shows poor acidity as the excess base is neutralized and a further 0.1 a 0.2 equivalents of an acid, it is preferable to add the crystallization cores of the type B crystals even at an earlier stage thereto. The amount of type B crystals to be added as seed is not particularly limited so long as the added crystals do not dissolve. However, the amount may generally be 0.01% or more based on the dissolved compound and, for example, the addition of preferably 0.05% or more, and particularly preferably about 0, may be mentioned. ,1%. Although the upper limit is not particularly limited, for example, 2% or less may generally be mentioned based on the compound and may be exemplified preferably 1.5% or less, more preferably 1.0% or less , and particularly preferably 0.3% or less. With respect to the method of collecting the precipitated crystals, the method of drying the collected crystals, the final concentration of the compound after the addition of the acid and the like, conditions which are the same as those described in the " Method of producing Type A crystals of Compound 1 of the invention " described above.

As preferred examples among the production methods described above the following can be exemplified. In the three examples of the production method which follow, the preferred examples described above may be used with regard to the amount of base used, the stirring temperature before the addition of the acid, the amount of acid to be added, the amount of B-type crystallization nuclei to be added and the stirring time after addition of acid.

A method of adding continuously over time, at a stirring temperature of 10 to 50Â ° C, to a solution of Compound 1 of the invention in water, methanol, ethanol, tetrahydrofuran or in a solvent mixture thereof containing 0.8 to 3.0 equivalents of sodium hydroxide or potassium hydroxide relative to 1 equivalent of said compound, an aqueous solution of 0.8 to 1.5 equivalents of hydrochloric acid, sulfuric acid or phosphoric acid relative to 1 equivalent of the base per a method such as dropwise addition; and in the medium of addition of the acid and when the pH of the solution is poor in pH 7 to 9, thereafter add the type B crystallization nuclei in an amount of 0.01 to 2% relative to said compound; and then stir for 1 to 24 hours to obtain the crystals.

A method of adding, over 1 hour to 6 hours, at a temperature of 25 to 45Â ° C under stirring, to a solution of Compound 1 of the invention in water, methanol, ethanol or a solvent mixture containing 0.9 to 2 , 0 equivalents of sodium hydroxide relative to 1 equivalent of said compound, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution to 1 equivalent of the base; and in the medium of addition of the acid and when the pH of the solution is poor in pH 7 to 9, thereafter add the type B crystallization cores therein in an amount of 0.05 to 1.5% relative to said compound; and then stir for 1 to 5 hours to obtain the crystals.

A method of adding over 1 hour to 6 hours at a temperature of 25 to 45Â ° C under stirring to a solution of Compound 1 of the invention in a mixture of methanol and 0.9 to 2.0 equivalents of an aqueous solution 0.5 to 2 N sodium hydroxide relative to 1 equivalent of said compound, 0.9 to

1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution to 1 equivalent of the base; and in the medium of the addition of the acid and when the pH of the solution is poor in pH 7 to 9, then add the type B crystallization cores 38 in an amount of 0.1% relative to the compound; and then stir for 1 to 5 hours to obtain the crystals.

In addition, as preferred examples of the production method, the following embodiments may be mentioned. In the three examples of the production method which follow, the preferred examples described above may be used with respect to the amount of the base used in the alkaline hydrolysis at the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before the addition of the acid, the amount of acid to be added, the amount of type B crystallization cores to be added and the stirring time after addition of the acid.

A method for allowing a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid lower alkyl ester to react in water, methanol, ethanol, tetrahydrofuran or a solvent mixture thereof in the presence of 1 to 3 equivalents of sodium hydroxide or potassium hydroxide relative to 1 equivalent of the lower alkyl ester at 50 to 70 ° C for 1 to 24 hours; subsequently continuously adding, at a stirring temperature of 10 to 50 ° C, 0.8 to 1.5 equivalents of an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid continuously with respect to 1 equivalent of the base by a method such as dropwise addition; and in the medium of the addition of the acid and when the pH of the solution is poor in pH 7 to 9, add thereto the type B crystallization nuclei in an amount of 0.01 to 2% relative to the compound; and then stir for 1 to 24 hours to obtain the crystals. 39

A method for allowing a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid methyl or ethyl ester to react in water , methanol, ethanol or a solvent mixture thereof in the presence of 1 to 2 equivalents of sodium hydroxide relative to 1 equivalent of the methyl or ethyl ester at 50 to 70øC for 1 to 24 hours, subsequently adding over 1 hour to 6 hours at 25-45 ° C under stirring, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution relative to the base; and in the medium of the addition of the acid and when the pH of the solution is poor in pH 7 to 9, add thereto the type B crystallization nuclei in an amount of 0.05 to 1.5% relative to the compound; and then stir for 3 to 24 hours to obtain the crystals.

A method of adding 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid methyl ester or ethyl ester, mixture of methanol and 1 to 2 equivalents of a 0.5 to 2 N aqueous sodium hydroxide solution to 1 equivalent of the methyl or ethyl ester, allowing the mixture to react at 50 to 70 ° C for 1 to 24 hours, subsequently add 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous hydrochloric acid solution over 1 equivalent of the base over 1 hour to 6 hours at 25-45øC under stirring; and in the medium of the addition of the acid and when the pH of the solution is poor in pH 7 to 9, add thereto the type B crystallization nuclei in an amount of 0.1% relative to the compound; and then stir for 3 to 24 hours to obtain the crystals. 40 [Method of producing crystals of Compound 2]

In addition, the crystal of Compound 2 is very advantageous in the formulation processes, insofar as it is easy to make the compound content constant in each preparation, and the like. In addition, the crystal is also favorable in that it is easy to remove its solvents and the like compared to the case of oily matter, and the invention of the method of producing the crystals advantageously enables the compound of the invention to be obtained with good purity without performing the purification by column chromatography which is necessary in the known production methods described above. Thus, the method is suitable for production on an industrial scale, which is extremely desirable.

As the method of producing the crystals of Compound 2 there may be mentioned a method of adding to a solution prepared by dissolving Compound 2 in a good solvent which readily dissolves the compound, a bad solvent in which the compound does not dissolve well to produce In this way the crystals of the compound are obtained, and the crystals are obtained. In the foregoing, Compound 2 may be prepared according to the method described in International Patent Publication No. WO 03/70686.

As the good solvent that is used for dissolving the compound, toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol and the like may be mentioned, and preferred are acetone, toluene, tetrahydrofuran and the like, with acetone. In addition, as the poor solvent which is added to produce crystals of the compound, heptane, diisopropyl ether, isopropanol, t-butyl methyl ether, water and the like may be mentioned. However, where acetone is used as the good solvent, water is preferred, and if toluene or tetrahydrofuran is used as the good solvent, heptane is preferred. A combined use of acetone as the good solvent and water as the bad solvent can be mentioned as a particularly preferred example.

For the concentration of the solution prepared with the good solvent, the upper limit is preferably 20% w / v or less, and more preferably 10% w / v or less, while the lower limit is preferably 5% w / v or more. For the amount of bad solvent to be added, the upper limit is preferably 2.0 times or less, preferably 1.5 times or less, and more preferably 1.1 times or less of the amount of the good solvent, while the lower limit is preferably 0.8 times or more, and more preferably 0.9 times or more than the amount of the good solvent. In particular, it is preferable to add an amount of 1.0 fold. In addition, addition of a quantity of 1.05 fold is another particularly preferred aspect. As a method of adding the bad solvent, a method of continuous addition over time is preferred by a method such as dropwise addition. When a poor solvent is added, stirring is preferred. The rate of addition may vary depending on the amount of the compound used, the concentration of the compound in the solution, the good solvent used and the type of bad solvent, but in case of addition of water as the bad solvent to a solution of the compound in acetone, an addition method over 1 hour to 3 hours is mentioned as an example. 42

For the temperature during the addition of the bad solvent, the upper limit is preferably 50 ° C or less, more preferably 40 ° C or less, and even more preferably 30 ° C or less, while the lower limit is preferably 0 ° C or more, more preferably 10 ° C or more, and even more preferably 20 ° C or more.

The generated crystals can be collected, for example, generally after 1 hour to 24 hours of the addition of bad solvent and preferably after 1 hour to 5 hours of addition.

As a method of collecting the precipitated crystals, the crystals may be obtained by known methods such as filtration and decantation, but filtration is generally preferred. In addition, after collection of the crystals by filtration, the crystals can be washed with a polar solvent such as water, acetone or a mixed solution thereof, and this process is effective to remove impurities.

The collected crystals may be dried by a generally accomplished drying method, such as drying under reduced pressure, drying under reduced pressure while heating, drying under normal pressure while heating, or drying in the air.

[Method of producing crystals of Compound 3]

In addition, the crystal of Compound 3 is very advantageous in the formulation processes in that it is easy to make the compound content constant in each preparation, and the like. In addition, the crystal is also favorable in that it is easy to remove the solvents and the like therefrom in comparison with the case of oily matter and the invention of the method of producing the crystals advantageously allows the compound of the invention to be obtained with without purification by column chromatography which is necessary in the known production methods described above. Thus, the method is suitable for production on an industrial scale, which is extremely preferred.

As a method of producing the crystals of Compound 3, there may be mentioned a method of adding, to a solution prepared by dissolving Compound 3 in a good solvent which readily dissolves the compound, a bad solvent in which the compound does not dissolve well, to produce In this way the crystals of the compound are obtained, and the crystals are obtained.

In the foregoing, Compound 3 may be prepared according to the method described in International Patent Publication No. WO 03/70686. In addition, the compound can be produced using a conventional methyl esterification reaction, for example, by esterification of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl- indazol-5-yl) phenyl] propionic acid methyl ester in a methanol solvent under acidic conditions, or the like.

As the good solvent which is used to dissolve the compound, there may be mentioned toluene, ethyl acetate, tetrahydrofuran, acetone and the like, and preferred are acetone, tetrahydrofuran and the like, with tetrahydrofuran being particularly preferred. Furthermore, as the bad solvent, heptane, isopropanol, methanol, water and the like may be mentioned. However, if acetone is used as a good solvent, water or heptane is preferred, and if tetrahydrofuran is used as a good solvent, heptane, isopropanol or water is preferred. A combined use of tetrahydrofuran as the good solvent and water as the poor solvent can be mentioned as a particularly preferred example.

For the concentration of the solution prepared with the good solvent, the upper limit is preferably 20% w / v or less, and more preferably 10% w / v or less, while the lower limit is preferably 5% w / v or more. For the amount of the bad solvent to be added, the upper limit is preferably 2.0 times or less, preferably 1.5 times or less, and more preferably 1.1 times or less of the amount of the good solvent, while the lower limit is preferably 0.8 times or more, and more preferably 0.9 times or more than the amount of the good solvent. In particular, it is preferable to add an amount of 1.0 fold. In addition, addition of a quantity of 1.05 fold is another particularly preferred aspect. As a method of adding the bad solvent, a method of continuous addition over time is preferred by a method such as dropwise addition. When a poor solvent is added, it is preferred to carry out stirring. The rate of addition may vary depending on the amount of the compound used, the concentration of the compound in the solution, the good solvent used and the type of bad solvent, but in the case of addition of water as the bad solvent to a solution of the tetra- A method of addition may be mentioned as an example over 1 hour to 3 hours.

As regards the temperature during the addition of the bad solvent, the upper limit is preferably 50 ° C or less, more preferably 40 ° C or less, and even more preferably 35 ° C or less , while the lower limit is preferably 0 ° C or more, more preferably 10 ° C or more, and even more preferably 25 ° C or more.

The crystals produced can be collected, for example, generally after 1 hour to 24 hours of the addition of bad solvent, and preferably after 1 hour to 5 hours of addition.

As a method of collecting the precipitated crystals, the crystals may be obtained by known methods, such as filtration and decantation, but filtration is generally preferred. In addition, after collection of the crystals by filtration, the crystals can be washed with a polar solvent, such as water, acetone or a mixed solution thereof, and this process is effective to remove impurities.

The collected crystals may be dried by a generally accomplished drying method, such as drying under reduced pressure, drying under reduced pressure while heating, drying under normal pressure while heating, or air drying.

The compounds of the invention suppress inflammatory edema in mice, allergic edema, contortion reaction by acetic acid and adjuvant arthritis in the rat by oral administration at a dose of 0.1 to 500 mg / kg, while causing no death between the mice by oral administration at a dose of 500 mg / kg / day for 3 days. Thus, the compounds are safe compounds as drugs for mammals, preferably humans, pets or companion animals such as dogs and cats, and livestock, and are useful substances as active pharmaceutical ingredients. As medicaments for mammals, preferably humans, pets or companion animals, such as dogs and cats, or farmed animals, any preferred prophylactic and / or therapeutic agents for the conditions, various diseases and conditions in which various acute or chronic inflammatory reactions resulting from the production of prostaglandins and / or leukotrienes, and specifically inflammatory diseases, allergic diseases, autoimmune diseases and pain are recognized.

To use the compounds of the invention as the medicaments described above, an effective amount of the compounds of the invention may be directly used or may be admixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition. This carrier may be exemplified by a suspending agent such as carboxymethylcellulose, or other known carriers may also be used. For example, a suspension method of the compounds of the present invention may be mentioned in purified water containing 0.5% carboxymethylcellulose.

Examples of the dosage form for formulating the above-mentioned pharmaceutical composition include tablets, powders, granules, syrups, suspensions, capsules, injections and the like. In view of the nature of the crystals of the compounds of the invention, it is particularly preferred that the pharmaceutical composition is a dry preparation. For the manufacture of such preparations various vehicles are used according to these preparations. For example, as the vehicle for oral preparations, excipients, binders, lubricants, flow promoters and colorants may be mentioned.

When the compounds of the present invention are formulated as a parenteral preparation such as an injection, distilled water for injectable preparation, saline, aqueous glucose solution, vegetable oils for injection, propylene glycol, polyethylene glycol and the like may generally be used as a diluent. According to the need, disinfectants, antiseptics, stabilizers, isotonic agents, soothing agents and the like may also be added.

In the case of administration of the compounds of the present invention to mammals, for example, humans, the compounds may be administered orally in the form of tablets, powders, granules, suspensions, capsules or the like, and may also be administered parenterally in the form including a drip infusion, a suppository, a gel, a lotion, an ointment, a cream or a spray formulation. The dose may vary depending on the disease to be administered, route of administration, age, weight and severity of the patient's symptoms, and the like, but in general an illustrative dose for an adult may be from 1 to 1000 mg per day, which is administered in 1 to 3 divided portions. The administration period is generally one daily administration for several days to two months. However, depending on the patient's symptoms, the daily dose and the period of administration may be increased or decreased.

As compounds analogous to the compounds described herein, the following compounds may be mentioned, and these compounds may also be prepared according to the method described in International Patent Publication No. WO 03/70686, or by the methods described in the present description. 3- [3-Amino-4- (indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid; 3- [3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (indan-2-yloxy) phenyl] propionic acid;

3- [4- (indan-2-yloxy) -3- (N-methylamino) -5- (1-methyl-1H-indazol-5-yl) ifenyl] propionic acid; 3- [4- (indan-2-yloxy) -5- (1H-indazol-5-yl) -3- (N-methylamino) phenyl] propionic acid; 3- [5- (1-Ethyl-1H-indazol-5-yl) -4- (indan-2-yloxy) -3- (N-methylamino) phenyl] propionic acid; 3- [3-Amino-4- (4-fluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers;

3- [3-Amino-4- (5-fluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) ifenyl] propionic acid and its isomers; 3- [3-Amino-4- (5,6-difluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid; 3- [3-amino-4-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) ifenyl] propionic acid and its isomers; 3- [3-amino-4- (4-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) ifenyl] propionic acid and its isomers; 3- [3-amino-4- (5-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) ifenyl] propionic acid and its isomers; 3- [3-amino-4- (5,6-dihydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid; 3- [3-Amino-4- (4-methoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (5-methoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (5,6-dimethoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid; 3- [3-Amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (5,6-dibenzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid; 3- [3-Amino-4- (4-fluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5-fluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5,6-difluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid; 3- [3-Amino-4- (1-hydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and its isomers; 50

3- [3-Amino-4- (4-hydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5-hydroxyindan-2-yloxy) -5- (1H-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5,6-dihydroxyindan-2-yloxazol-5-yl) phenyl] propionic acid; 3- [3-amino-5- (1H-indazol-5-yl) -4- (4-methoxyoxy) phenyl] propionic acid and its isomers; 3- [3-Amino-5- (1H-indazol-5-yl) -4- (5-methoxyoxy) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5,6-dimethoxyindan-2-yloxy) -5-yl) phenyl] propionic acid; 3- [3-amino-4- (4-benzyloxyindan-2-yloxazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (4-benzyloxyindan-2-yloxazol-5-yl) phenyl] propionic acid and its isomers; 3- [3-amino-4- (5,6-dibenzyloxyindan-2-yloxazol-5-yl) phenyl] propionic acid; 3- [3-Amino-5- (1-ethyl-1H-indazol-5-fluoroindan-2-yloxy) phenyl] propionic acid and its isomers; 3- [3-Amino-5- (1-ethyl-1H-indazol-5-fluoroindan-2-yloxy) phenyl] propionic acid and its isomers; indol-1-yl) -5- (1H-iindan-2-ylindan-2- (indazol-i) -5- (1H-i) -5- (1H-i) -5- (1H-yl) -4- 3- (3-Amino-4- (5,6-difluoroindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers 3- [3-Amino-5- (1-ethyl-1H-indazol-5-yl) -4- (1-hydroxyindan-2-yloxy) phenyl] (3-amino-5- (1-ethyl-1H-indazol-5-yl) -4- (4-hydroxyindan-2-yloxy) phenyl] propionic acid and its isomers; (1-ethyl-1H-indazol-5-yl) -4- (5-hydroxyindan-2-yloxy) phenyl] propionic acid and the isomers thereof 3- [3-Amino-4- (5,6- 3- (3-Amino-5- (1-ethyl-1H-indazol-5-yl) -phenyl] propionic acid; 3- (3-Amino-5- (1-ethyl-1H-indazol-5-yl) -4- (5-methoxyindan- 2-yloxy) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (5,6-dimethoxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl ] propionic acid 3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-ethyl-1H-ind azol-5-yl) phenyl] propionic acid and its isomers; 3- [3-Amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid and its isomers; and 3- [3-amino-4- (5,6-dibenzyloxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid. 52

EXAMPLES Hereinafter, the present invention will be described in more detail by means of Examples and Test Examples, but the present invention is not limited thereto. (EXAMPLE 1)

Preparation Example 1 for methyl 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] propionate crystals (Compound 2)

THF (40 mL) was added to methyl 3- [3-bromo-4- (indan-2-yloxy) -5-nitrophenyl] propionate (14.00 g, prepared according to the method of International Patent Publication No. No. WO 03/70686), 1-methyl-1H-indazole-5-boronic acid (7.62 g, prepared according to the method of International Patent Publication No. WO 03/70686), palladium acetate (75 mg , Wako Pure Chemical Industries, Ltd.) and triphenylphosphine (0.17 g, Wako Pure Chemical Industries, Ltd.), and the mixed solution was stirred. Then, a solution having potassium triphosphate (16.97 g, Wako Pure Chemical Industries, Ltd.) dissolved in water (27 mL) was added to the above mixture, and the mixed solution was purged with nitrogen. This mixed solution was then stirred for 4 hours at 60 ° C to react. After confirming completion of the reaction, the reaction solution was partitioned to give the topsheet. The topsheet was cooled to room temperature, ethyl acetate (40 mL) and activated charcoal (2.8 g, Japan Envirochemicals, Ltd.) were added thereto, and the mixed solution was further stirred for 1 hour at room temperature. The suspension was filtered to obtain a filtrate, and the residue was washed on the filter with ethyl acetate (20 mL) to give the wash solution. The filtrate and wash solution were combined and concentrated under reduced pressure to give a concentrate (44 g). Then, acetone (140 mL) was added to the concentrate. The mixed solution was stirred and water (140 mL) was added thereto over 1 hour under stirring. The mixed solution was further stirred for an additional 1 hour at room temperature. This mixed solution was then filtered, the solids were washed on the filter with water (70 mL) and wet solids were obtained. These wet solids were dried under reduced pressure at 50 ° C to give crystals of the title compound (15.7 g). (EXAMPLE 1-A, B)

Preparation Example 2 for crystals of Compound 2

The crystals of the compound can be obtained according to the procedures of Example 1 except for the addition of toluene instead of acetone to the concentrate, and addition of heptane instead of water.

The Compound 2 crystals of the invention may also be obtained by adding tetrahydrofuran instead of acetone, and using heptane instead of water as used in Example 1. EXAMPLE 2

Preparation Example 1 Methyl 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionate (Compound 3)

To compound 2 (13.0 g) prepared according to Example 1 were added THF (138 mL), stabilized nickel (4.42 g, NIKKI CHEMICAL CO., LTD.) And water (4 mL), the mixed solution was stirred, then the interior of the system was purged with hydrogen and the system was allowed to react under an atmosphere of hydrogen at 50øC for 7 hours under stirring. After confirming completion of the reaction, the reaction solution was purged with nitrogen and filtered to obtain a filtrate, and the residue was washed on the filter with THF (34 mL) to provide a wash solution. The filtrate and washing solution were combined, activated charcoal (2.6 g, Japan Envirochemical Co., Ltd.) was added to the combined solution and the mixed solution was stirred for 1 hour at room temperature. The suspension was filtered to obtain a filtrate and the residue was washed on the filter with THF (34 mL) to give a wash solution. Then the filtrate obtained and the wash solution were combined, water (207 mL) was added to the combined solution over 1 hour, and the mixed solution was stirred for an additional 1 hour under ice-cooling. Then, this mixed solution was filtered and the solids were washed on the filter with water (68 mL) to obtain wet solids. These wet solids were dried under reduced pressure at 50 ° C to give crystals of the title compound (10.3 g). 55 (EXAMPLE 2-A, B)

Preparation Example 2 for Compound 3

The crystals of compound 3 can be obtained by adding heptane to the combined filtrate solution and wash solution instead of water as used in Example 2.

In addition, the crystals of Compound 3 can be obtained using isopropanol as the solvent. (EXAMPLE 3)

Preparation Example 1 of the type A crystal of Compound 1 of the invention

Methanol (45 mL) was added to Compound 3 of the invention (10.0 g) obtained in Example 2 and the solution was stirred. A 2N aqueous sodium hydroxide solution (17.0 mL) was added to the above solution and the mixture was stirred for 3 hours at 60 ° C to perform alkaline hydrolysis. After the reaction the reaction solution was cooled to 35øC and 2N aqueous hydrochloric acid solution (17.0 ml) was added thereto over 2 hours, which was further stirred for 16 hours at 35øC. This mixed solution was then filtered and the solids were washed on the filter with a mixture of water (27 mL) and methanol (13 mL) to provide wet solids. These wet solids were dried under reduced pressure at 50 ° C to obtain 9.2 g of crystals. 56 (EXAMPLE 4)

Preparation Example 1 for the type B crystal of Compound 1 of the invention

Acetone (17 mL) was added to the Type A crystals of Compound 1 of the invention (1.0 g) prepared according to Example 3 and the mixture was heated in a water bath at 60 ° C to dissolve the crystals. Thereafter, the solution was stirred overnight at room temperature. The precipitate generated was filtered and solids were obtained on the filter. The solids were then dried under reduced pressure at 50 ° C to obtain 0.55 g of crystals. (EXAMPLE 5)

Preparation Example 2 for the type B crystal of Compound 1 of the invention

Dichloromethane (31 mL) was added to the Type A crystals of Compound 1 of the invention (1.0 g) prepared according to Example 3 and the mixture was heated in a water bath at 40 ° C to dissolve the crystals. Thereafter, the solution was stirred overnight at room temperature. The precipitate produced was filtered and solids were obtained on the filter. The solids were then dried under reduced pressure at 50 ° C to give 0.81 g of crystals.

The crystals showed a spectrum which is substantially identical to Fig. 7 in a differential scanning calorimetric analysis according to Test Example 4 which will be described later, and was thus confirmed to be a type B crystal of Compound 1 of the invention. (EXAMPLE 6)

Preparation Example 3 for the B-type crystal of Compound 1 of the invention

Methanol (45 mL) was added to the Type A crystals of Compound 1 of the invention (10.0 g) prepared according to Example 3 and the mixture was stirred. Thereafter, 2N aqueous sodium hydroxide solution (17.0 mL) was added to the mixture and the mixed solution was stirred for 1 hour at 60 ° C. This mixed solution was cooled to 35øC and 2N aqueous hydrochloric acid (7.0 mL) was added thereto over 30 minutes. After confirming that the pH of the mixed solution had reached 7 to 9, the crystallization cores of the Type B crystals of Compound 1 of the invention (0.1 g) prepared according to Example 4 were immediately added and the mixed solution was still stirred for 10 minutes. Thereafter, 2N aqueous hydrochloric acid solution (10.0 mL) was added to this mixed solution over 1 hour and the mixed solution was stirred for 2 hours at 35 ° C. This mixed solution was then filtered and the solids were washed on the filter with a mixed solution of water (27 mL) and methanol (13 mL) to provide wet solids. These wet solids were dried under reduced pressure at 50 ° C to obtain 9.7 g of white crystals.

The crystals showed a spectrum which is substantially identical to Fig. 6 in an X-ray diffraction measurement according to Test Example 3 which will be described below, and thus confirmed to be a type B crystal of Compound 1 of the invention. In addition, the crystals showed a spectrum which is substantially identical to Fig. 7 in a differential scanning calorimetric analysis according to Test Example 4 which will be described below, and was thus confirmed to be a type B crystal of the Compound 1 of the invention. (EXAMPLE 7)

Preparation Example 4 for the type B crystal of Compound 1 of the invention

Methanol (360.0 mL) was added to Compound 3 (80.0 g) obtained by a procedure according to Example 2 and the mixture was stirred. Then water (36.2 mL) and a 2N aqueous sodium hydroxide solution (99.7 mL) were added to the mixture, and the resulting solution was subjected to alkaline hydrolysis under stirring at 60 ° C for 3 hours. After the reaction, impurities such as a fine dust in the reaction solution were separated by filtration, water (180.2 mL) was added and then the mixed solution was adjusted to 35øC. A 2N aqueous hydrochloric acid solution (10.7 mL) was added to the mixed solution over 8 minutes, and after confirming that the pH of the mixed solution had reached 7.9, the crystal crystallization cores were immediately added of type B of Compound 1 of the invention (0.08 g) prepared according to Example 4, and the resulting mixture was stirred for 4 minutes. Thereafter, 2N aqueous hydrochloric acid solution (89.0 mL) was added to this mixed solution over 111 minutes and the solution was stirred for 14.3 hours at 35 ° C. This mixed solution was then filtered and the solids were washed on filter 59 with a mixed solution of water (213.4 mL) and methanol (106.7 mL) to provide wet solids. To these wet solids, water (213.4 mL) and methanol (106.7 mL) were again added to form a mixed solution, and stirred for 37 minutes at 18 to 20 ° C. This mixed solution was then filtered and the solids washed on the filter with a mixed solution of water (21.3 mL) and methanol (10.7 mL) to provide wet solids. These wet solids were dried under reduced pressure at 50øC to obtain 76.28 g of white crystals.

These crystals showed a spectrum which is substantially identical to Fig. 7 in a differential scanning calorimetric analysis according to Test Example 4 which will be described below, and was thus confirmed to be a type B crystal of Compound 1 of the invention. invention. (EXAMPLE 8)

Preparation Example 1 for mixed crystals of Compound 1 of the invention

0.9 g of type A crystals of Compound 1 of the invention prepared according to Example 3 and 0.1 g of type B crystals prepared according to Example 4 were mixed using a mortar and pestle and was obtained a mixture containing 90% of type A crystals and 10% of type B crystals. (EXAMPLE 9)

Preparation Example 2 for mixed crystals of Compound 1 of the invention

0.1 g of Type A crystals of Compound 1 of the invention prepared according to Example 3 and 0.9 g of type B crystals prepared according to Example 4 were mixed using a mortar and pestle and obtained a mixture containing 10% of type A crystals and 90% of type B crystals. (EXAMPLE 10)

Preparation Example 2 for Type A crystal of Compound 1 of the invention Compound 3 (3.92 kg) obtained by a method according to

Example 2 was introduced into a reaction apparatus A (instrument number: BD-1, 30 L vertical type reaction apparatus,

ASAHI TECHNO GLASS CORPORATION), methanol (14.08 kg) was added thereto and the mixed solution was stirred. After adding 2N aqueous sodium hydroxide solution (6.76 kg), the mixed solution was heated to 60.6 ° C over 27 minutes. The mixed solution was stirred at about 60 ° C for 4 hours and 9 minutes, then cooled to 35 ° C over 19 minutes and the reaction solution was filtered through a membrane filter to prepare a reaction solution 1. In addition, Compound 3 (3.92 kg) obtained according to a method according to Example 2 was introduced into reaction apparatus A, there was added methanol (14.25 kg) therein and the mixed solution was stirred. After adding 2N aqueous sodium hydroxide solution (6.70 kg), the mixed solution was heated to 60øC over 30 minutes. The mixed solution was stirred at about 60 ° C for 4 hours and 30 minutes and then cooled to 34.6 ° C over 17 minutes, the reaction solution was filtered through a membrane filter and the filtrate was combined with reaction solution 1 in a reaction apparatus B (instrument #: BD-2, 100 L vertical type reaction apparatus, ASAHI TECHNO GLASS CORPORATION) to prepare a reaction solution 2. This reaction solution 2 was maintained at 30 to 35 ° C and a 2N aqueous hydrochloric acid solution (13.30 kg) was added dropwise over 5 hours 48 minutes under stirring to the precipitated crystals, thereby preparing a precipitate solution. Then, while maintaining this precipitate solution at about 35øC, the precipitate solution was stirred for 10 hours and 5 minutes, and then introduced into a filter vessel (Instrument No. F-9, Nutsche filter of (J > 6.00, ASAHI ENGINEERING CO., LTD.) And aspiration filtration was performed to obtain wet crystals. To the wet crystals in this filtration vessel, a mixed solution of water (20.00 kg) was aspirated and aspirated. In addition, the aspiration continued to dehydrate sufficiently and wet crystals of the type A crystal of Compound 1 of the invention (15.571 kg) were obtained. wet crystals were obtained from the precipitate solution by filtration was 1 hour and 5 minutes, the time required to wash the wet crystals in the filter vessel with a mixed solution of water and methanol was 1 hour and 44 minutes, and the temp the necessary for dehydration was 50 minutes. These wet crystals were scattered in a tray and placed in a greenhouse (instrument #: BM-6, compartmentalized tray vacuum oven, VAC-300PR, Spec Corporation), and dried under reduced pressure at 50øC for 62 days over 65 hours and 52 minutes) to obtain the type A crystals of Compound 1 of the invention (7, 402 kg).

The crystals showed a spectrum which is substantially identical to Fig. 3 in an X-ray diffraction measurement according to Test Example 3 which will be described below, and was thus confirmed to be a type A crystal of Compound 1 of the invention. In addition, the crystals showed a spectrum which is substantially identical to Fig. 4 in a differential scanning calorimetric analysis according to Test Example 4 which will be described below, and was thus confirmed to be a type A crystal of the Compound 1 of the invention. (EXAMPLE 11)

Compound 3 (3.90 kg) obtained by a method according to Example 2 was introduced into a reaction apparatus A (instrument number: BD-1, reaction apparatus 30 L vertical type, ASAHI TECHNO GLASS CORPORATION), methanol (13.75 kg) was added thereto and the mixed solution was stirred. After adding 2N aqueous sodium hydroxide solution (5.20 kg) and water (1.75 kg), the mixed solution was heated to 60øC over 42 minutes. The mixed solution was stirred at about 60 ° C for 2 hours and 29 minutes and then cooled to 35.0 ° C over 13 minutes, and the reaction solution was filtered through a membrane filter to prepare a reaction solution 1. In addition, Compound 3 (3.90 kg) obtained by a method according to Example 2 was introduced into a 63 A reaction apparatus, methanol (13.97 kg) was added thereto and the mixed solution was stirred. After adding 2N aqueous sodium hydroxide solution (5.20 kg) and water (1.75 kg), the mixed solution was heated to 60øC over 40 minutes. The mixed solution was stirred at about 60 ° C for 2 hours and 34 minutes, then cooled to 35.0 ° C over 19 minutes, and the reaction solution was filtered through a membrane filter, and the filtrate was combined with reaction solution 1 in a reaction apparatus B (instrument #: BD-2, 100 L vertical type reaction apparatus, ASAHI TECHNO GLASS CORPORATION) to prepare a reaction solution 2. After adding water (17.36 kg ) to reaction solution 2, this reaction solution 2 was maintained at 30 to 35øC, an aqueous solution of 2N hydrochloric acid (0.92 kg) was added dropwise over 38 minutes under stirring, and dropwise addition was stopped at a time when the pH reached 7.90. Then, type B crystals of Compound 1 of the invention (7.795 g) were added and then aqueous 2N hydrochloric acid (9.08 kg) was added dropwise over 3 hours and 50 minutes to thereby precipitating the crystals and preparing a precipitate solution. Further, this precipitate solution was stirred for 8 hours and 42 minutes while being maintained at about 35øC, and then was introduced into a filter vessel

(instrument #: F-9, Nutsche filter of φ600; ASAHI ENGINEERING CO., LTD.), and suction filtration was performed in the same manner as in Example 10 to obtain wet crystals. To the wet crystals in this filtration vessel, a mixture of water (20.78 kg) and methanol (8.10 kg) was poured and aspirated to wash the wet crystals. Further, the aspiration continued until sufficiently dehydrated and wet crystals of the type B crystal of Compound 1 of the invention were obtained. At this point, the time required to obtain the wet crystals from the precipitate solution by filtration was 8 minutes, the time required to wash the wet crystals in the filter vessel with a mixture of water and methanol was 10 minutes, and time required for dehydration was 37 minutes. To increase the purity of these wet crystals, a mixture of water (21.00 kg) and methanol (8.18 kg) was added to obtain a suspension, and the suspension was stirred for 34 minutes and washed. This suspension was then introduced into a filter vessel (instrument #: F-9, Nutsche filter of φβΟΟ, ASAHI ENGINEERING CO., LTD.). Then, a mixed solution of water (2.10 kg) and methanol (0.80 kg) was introduced into the filtration vessel, and aspiration filtration was performed to obtain wet crystals. Thereafter, the aspiration continued to dehydrate sufficiently to thereby obtain wet crystals of the type B crystal of Compound 1 of the invention (12,211 kg). At this point, the time required until wet crystals were obtained from the suspension by filtration was 4 minutes and the time required for dehydration was 16 minutes. These wet crystals were scattered in a tray and placed in a greenhouse (instrument #: BM-6, compartmentalized tray vacuum oven, VAC-300PR, Spec Corporation) and dried under reduced pressure at 50 ° C for 3 days (over 71 hours and 3 minutes) to obtain the B-type crystals of Compound 1 of the invention (7.412 kg).

The crystals showed a spectrum which is substantially identical to Fig. 6 in an X-ray diffraction measurement according to Test Example 3 which will be described below, and was thus confirmed to be a type B crystal of Compound 1 of the invention. In addition, the crystals showed a spectrum which is substantially identical to Fig. 7 in a differential scanning calorimetric analysis according to Test Example 4 which will be described below, and was thus confirmed to be a type B crystal of Compound 1 of the invention. (TEST EXAMPLE 1)

Measuring the filtration rate 1

To the type A crystals of Compound 1 of the invention (5.0 g) prepared according to Example 3, a mixed solution of methanol and water (1: 2 mixture ratio) (50 ml) was added, the resultant stirred for 30 minutes at 25 ° C, and then a Kiriyama funnel (inner diameter 40 mm, Kiriyama funnel filter paper No. 3) and a vacuum cleaner for filtration were used. At that time, it took 2 minutes and 37 seconds to obtain 10 mL of a filtrate, it took 7 minutes and 45 seconds to obtain 20 mL of a filtrate, it took 15 minutes and 14 seconds to obtain 30 mL of a filtrate, and finally , it took 25 minutes and 24 seconds to obtain 40 mL of a filtrate. Then the wet solids in the funnel were dried under reduced pressure at 50 ° C to give 4.9 g of crystals.

To the type B crystals of Compound 1 of the present invention (5.0 g) prepared according to Example 4, a mixed solution (50 mL) of methanol: water (1: 2) was added, the resulting was stirred for 30 minutes. minutes at 25 ° C and filtration was performed using a Kiriyama funnel (40 mm internal diameter, Kiriyama # 3 funnel filter paper) and a vacuum cleaner was used for filtration. At that time, it took 8 seconds to obtain 10 ml of a filtrate, it took 17 seconds to obtain 20 ml of a filtrate, it took 28 seconds to obtain 30 ml of a filtrate, and finally it took 2 minutes to obtain 42 ml of a filtrate. Then the wet solids in the funnel were dried under reduced pressure at 50 ° C to obtain 4.7 g of crystals.

As described above, the time required to obtain type B crystals may be one tenth or less compared to the time required to obtain type A crystals and thus the excellent filtrability of the type B crystal of the present invention has been confirmed. (TEST EXAMPLE 1-2)

Measurement of the filtration rate 2 The fragility of the type A crystal of Compound 1 of the invention of Example 10 was compared to the filtrability of type B crystal of Compound 1 of the invention of Example 11. For each case, the required time intervals in three steps, such as (1) the time required to separate the wet crystals from the mother liquor by aspiration from the introduction of the precipitate solution into a filtration vessel, (2) then the time required for washing the deposited crystals in the filter vessel by aspiration from the introduction of a washing mixture of water and methanol, and (3) finally, the time required to sufficiently reduce the humidity of the wet crystals followed by aspiration from the end of the wash . For type A crystals, it took (1) 1 hour 5 minutes, (2) 1 hour 44 minutes and (3) 50 minutes, while for Type B crystals, it took (1) 8 minutes, (2) minutes and (4) 37 minutes. Thus, the excellent filterability of the type B crystal of the invention could be confirmed. (TEST EXAMPLE 1-3)

Measurement of water content after filtration

The respective water contents of the crystals obtained in Example 10 and Example 11 were calculated from the weight of the wet crystals and the weight of the crystals upon drying. The water contents were 52.5% and 39.3% for type A crystal and type B crystal, respectively. Thus, the drying properties of the type B crystal of the present invention were excellent. The results are shown in Table 1. In Example 10 and Example 11 both were dried for 3 days but in practice it can be easily conjectured that type B crystal having a low water content would require less time and energy to dry .

[Table 1]

Measurement results for water content

Crystal Weight of wet crystals (kg) Weight of crystals after drying (kg) Water content (%) Type A crystal (Example 10) 15.571 7, 402 52.5 Type B crystal (Example 11) 12,211 7,412 39 , 688 (TEST EXAMPLE 2)

Solubility test

The type A crystals of the compound 1 of the invention prepared according to Example 3 and the type B crystals of the compound 1 of the invention prepared according to Example 4 were respectively weighed to 10 mg in a 10 ml centrifuge tube, were respectively added to each 3 ml of the liquid of the Japanese Pharmacopoeia disintegration test (pH 1.2) and the solutions of the mixtures were stirred for 24 hours at 37 ° C. After stirring, the solutions were filtered, exactly 1 mL of each filtrate was pipetted and exactly 1 mL of acetonitrile was added to obtain a sample solution.

The sample solutions were analyzed using the HPLC technique with the following conditions and the concentration of the compound in the sample solution was determined by comparing it with that of a standard solution having a known concentration under the following HPLC conditions, to determine the solubility. The same assay was performed with the 2nd disintegration test liquid from the Japanese Pharmacopoeia (pH 6.8) to determine the solubility.

The results are presented in Table 3. 69 [Table 2] Conditions

Injection volume: 10 pL

Detector: Ultraviolet absorption spectrometer (wavelength: 235 nm)

Mobile phase: 50 mmol / L sodium dihydrogen phosphate / acetonitrile (55:45)

Column: YMC-Pack Pro C18, inner diameter: 4.6 mm, length: 15 cm (YMC Corporation)

Column temperature: 40 ° C

Flow rate: 1.0 mL / min [Table 3] Solubility test results

Crystal Solubility in the 1st liquid of the Japanese Pharmacopoeia disintegration test (pH 1.2) (mg / mL) Solubility in the 2nd liquid of the Japanese Pharmacopoeia disintegration test (pH 6.8) (mg / mL) Type A crystal 0.03 0.06 Crystal type B 0.01 0.02

As shown in Table 3, the solubilities of the type A crystal in the liquid of the Japanese Pharmacopoeia disintegration test (pH 1.2) and 2nd liquid of the Japanese Pharmacopoeia disintegration test (PH 6.8) were three times larger than those of type B crystals, and the high solubility of the type A crystal of the present invention could be confirmed. 70 (TEST EXAMPLE 3)

X-ray Diffraction X-ray diffraction analysis was performed for the crystals obtained in the respective Examples of the present disclosure.

[Table 4] Measurement Conditions

X-ray diffraction apparatus: XRD-6000 manufactured by SHIMADZU CORPORATION

X-ray source: CuKoi (40 kV, 30 mA)

Scan Mode: Continuous Scan Rate: 2 ° / min Scan Step: 0.02 °

Scan orientation axis: Θ-2Θ Scan range: 5 ° to 40 °

Dispersion slit: Io Incision slit: 0.30 mm

The measurement results are as follows.

The crystals of Compound 2 obtained by a method according to Example 1 were measured and the spectrum shown in Fig. 1 was obtained. In the X-ray diffraction spectrum of the crystals of Compound 2, characteristic peaks were observed at 2θ of 7, 6 °, 15.3 °, 18.0 °, 21.3 ° and 26.9 °. Peaks were also observed at any or all of 16.3 °, 20.4 °, 23.0 ° or 30.5 °, and any of these may also be interpreted at least as characteristic peaks. In addition, peaks at any or all of 11.5 °, 19.1 °, 25.1 ° or 25.8 ° have also been observed, and any of these may also be interpreted at least as characteristic peaks. These crystals were evaluated as being crystals even from the morphological observation with the naked eye and was also confirmed from the analysis data described above which were crystals.

In addition, the crystals of Compound 3 obtained by a method according to Example 2 were measured and the spectrum shown in Fig. 2 was obtained. In the X-ray diffraction spectrum of the crystals of Compound 3, characteristic peaks were observed at 2θ of 8.6 °, 12.7 °, 17.2 °, 17.6 °, 18.9 ° and 21.0 °. Peaks were also observed at any or all of 14.7 °, 18.4 °, 19.4 ° or 22.1 °, and any of these may also be interpreted at least as characteristic peaks. In addition, peaks were also observed at any or all of 11,9 °, 14,2 °, 23,0 °, 24,7 °, 26,1 °, 26,8 ° or 32,6 °, and any of these can also be interpreted at least as characteristic peaks. These crystals were evaluated as being crystals even from the morphological observation with the naked eye and was also confirmed from the analysis data described above which were crystals.

The type A crystals of Compound 1 of the invention were measured by a method according to Example 3 and the spectrum shown in Fig. 3 was obtained. In the X-ray diffraction spectrum of the type A crystals of Compound 1 of the invention , characteristic peaks at 2θ of 6.9ø, 14.4ø, 16.4ø, 18.2ø, 25.0ø and 27.5ø were observed. Peaks were also observed at any or all of 20.0 °, 20.7 °, 22.9 ° or 25.4 °, and any of these may also be interpreted at least as characteristic peaks. In addition, peaks at any or all of 10.2 °, 12.7 °, 15.0 ° or 23.8 ° have also been observed, and any of these may also be interpreted at least as characteristic peaks.

Type B crystals of Compound 1 of the invention were measured by a method according to Example 6 and the spectrum shown in Fig. 6 was obtained. In the X-ray diffraction spectrum of the B-type crystals of Compound 1 of the invention, characteristic peaks at 2Θ of 14.4 ', 15.9ø, 17.3ø, 22.2ø and 22.9ø were observed. Peaks were also observed at any or all of 8.6 °, 9.8 °, 21.2 °, 23.6 ° or 28.4 °, and any of these may also be interpreted at least as characteristic peaks. In addition, peaks were also observed at any or all of 12.6 °, 18.0 °, 18.3 °, 18.8 °, 19.2 °, 19.8 °, 20.4 °, 25.3 26.6 ° or 31.8 °, and any of these may also be interpreted at least as characteristic peaks. (TEST EXAMPLE 3-2) Method of measuring crystalline purity

When calculating the rate of contamination in case a crystalline type of Compound 1 of the invention contaminates another type of crystal, it is suggested that an X-ray diffraction spectroscopic measurement is performed under the following conditions using a parallel beam optical system with a rotating sample platform. Describing specifically by taking as an example the case where type A crystal contaminates type B crystals, type A crystals are used which are crystalline pure as standard material and a suitable peak is selected from the characteristic peaks of type A crystal ( the appropriate peak can be exemplified by a peak at 73 ± 0.9 ° C). In relation to this peak, the peak intensity of the standard material and the peak intensity of a sample to be measured are compared; i.e., the peak intensity of the sample to be measured is divided by the peak intensity of the standard material, whereby the proportion of contamination of type A crystals in the sample can be calculated.

[Table 5] Measurement conditions

X-ray diffraction apparatus: RINT 2200 Ultima + / PC manufactured by Rigaku Corporation Measurement method: Parallel beam method using rotating sample platform

X-ray source: CuKa (40 kV, 30 mA)

Scan Mode: Continuous Scan Rate: 2 ° / min Scan Step: 0.02 °

Scan orientation axis: Θ-2Θ Scan range: 3 ° to 40 °

Slit: open Slit: open

Rotation speed of the sample platform: 120 rpm (TEST EXAMPLE 4)

Differential scanning calorimetric analysis

1 to 3 mg of the crystals obtained in Example 3 or 4 of the present disclosure were placed in an open aluminum vessel, and the measurement was performed under a dry nitrogen atmosphere of 50 ° C to 74 220 ° C at a heating rate of 10 ° C / min using a DSC PYRIS Diamond differential scanning calorimetry apparatus manufactured by PerkinElmer, Inc. Alternatively, the measurement was performed at 50 ° C to 220 ° C at a heating rate of 10 ° C / min using a differential scanning calorimetric measuring device DSC DSC3200 manufactured by Bruker AXS KK

The results are as follows.

A measurement was made with the type A crystals of Compound 1 of the invention obtained by a method according to Example 3 and, as a consequence, the graph shown in Fig. 4 was obtained. In the differential scanning calorimetric analysis of the type crystals A of Compound 1 of the invention, an endothermic peak was observed at about 182 ° C. In addition, no particular peak has been observed suggesting the existence of a hydrate or a solvate.

In addition, a measurement was made with the Type B crystals of Compound 1 of the invention obtained by a method according to Example 4 and, as a consequence, the graph shown in Fig. 7 was obtained. In the differential scanning calorimetric analysis of the Type B crystals of Compound 1 of the invention, an endothermic peak was observed at about 203 ° C. In addition, no particular peak has been observed suggesting the existence of a hydrate or a solvate.

Moreover, it was found that the graph of the crystals prepared in Example 10 was substantially identical to Fig. 4 and thus was type A crystal. In addition, the crystal graphics prepared in Examples 5 to 7 and 11 , 75 respectively, were also substantially identical to Fig. 7 and were suggested to be type B crystal.

According to the present invention, there is no particular problem if the compounds of the invention are in the hydrate or solvate form, but it is more preferred that they are anhydrides or non-solvates. (TEST EXAMPLE 5)

Spectroscopic absorption analysis in infrared

With respect to the crystals obtained by the methods according to Example 3 or 6 of the present description, the measurement was done by a disk method of potassium bromide.

The results are as follows.

A measurement was made with the type A crystals of Compound 1 of the invention obtained by a method according to Example 3, and as a consequence, the spectrum shown in Fig. 5 was obtained. As a consequence, in the absorption spectrum in the infrared absorption of the Type A crystals of Compound 1 of the invention, significant infrared absorption bands were observed at wave numbers 3361, 2938, 1712, 1204, 1011 and 746 cm -1.

Infrared absorption bands were also observed at any or all of 3443, 3349, 1620, 1515, 1480 or 1278 cm -1, and any of these may also be interpreted at least as characteristic peaks. In addition, infrared absorption bands were also observed at any or all of 3473, 1585, 1432, 1343, 1159, 781 or 615 cm -1, and any of these 76 may also be interpreted at least as characteristic peaks.

In addition, a measurement was made with the Type B crystals of Compound 1 of the invention obtained by a method according to Example 6, and as a consequence, the spectrum shown in Fig. 8 was obtained. As a consequence, in the spectrum of infrared absorption of type B crystals, significant infrared absorption bands were observed at wave numbers 2939, 1720, 1224, 1016 and 751 cm -1. Infrared absorption bands have also been observed at any or all of 3407, 3358, 1513, 1476 or 852 circ1, and any of these may also be interpreted at least as characteristic peaks. In addition, infrared absorption bands were also observed at any or all of 3447, 3325, 1615, 1339, 1157, 945, 783 and 617 cm -1 and any of these may also be interpreted at least as characteristic peaks. (TEST EXAMPLE 6)

Quantitative measurement of crystals

0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8, or 3.2 mg of a standard material of the type A crystal of Compound 1 of the invention was placed in a container and the measurement was carried out in a dry nitrogen atmosphere at 50Â ° C to 220Â ° C at a heating rate of 50Â ° C / min using a PYRIS Diamond DSC differential scanning calorimetry apparatus manufactured by PerkinElmer, Inc .

the area (mJ) of an endothermic peak was determined at about 185 ° C and a calibration curve was prepared for quantification of type A crystals.

0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8, or 3.2 mg of a standard B crystal type material of Compound 1 of the invention was also provided opened aluminum vessel and was measured in a dry nitrogen atmosphere from 50 ° C to 220 ° C at a heating rate of 50 ° C / min using a PYRIS Diamond DSC Differential Scanning Calorimeter manufactured by PerkinElmer, Inc. Thus the (mJ) area of an endothermic peak was determined at about 205øC and a calibration curve was prepared for quantification of type B crystals. The calibration curve for type A crystal is shown in Fig .

In addition, the calibration curve for type B crystal is shown in Fig.

It was found that it was possible to quantify with both type A crystals and type B crystals.

In addition, as standard crystal type A material, a measurement was performed using crystals which were obtained according to the method of Example 3 of the present disclosure, were in particular a preferred form, and presented a unique characteristic endothermic peak in the calorimetric analysis of differential scanning.

In addition, as standard crystal type B material, a measurement was performed using crystals which were obtained according to the method of Example 4 of the present disclosure, were in particular a preferred form, and presented a unique characteristic endothermic peak in the analysis differential scanning calorimetry. (TEST EXAMPLE 7)

Quantification of the compounds of the invention The detection and quantification of the compounds of the invention were performed under the following HPLC conditions.

[Table 6] Conditions

Sample concentration: 0.2 mg / ml (Compounds 1 of the invention and 3: dissolved in a mixed solution of water / acetonitrile (1: 1)

Compound 2: dissolved in acetonitrile)

Injection volume: 10 pL

Detector: Ultraviolet absorption spectrometer (wavelength: 235 nm)

Column: YMC-Pack Pro C18, inner diameter: 4.6 mm, length: 15 cm (YMC Corporation)

Column temperature: 40 ° C

Mobile phase A: 50 mmol / L sodium dihydrogen phosphate

Mobile phase B: acetonitrile

Gradient Program: The concentration gradient is controlled by changing the ratio of the blend of the mobile phase A and the mobile phase B as shown in Table 7.

Flow rate: 1.0 mL / min [Table 7] Gradient program

Time Lapse After Injection (min) Mobile Phase A (%) Mobile Phase B (%) 0-45 65 ^ 20 35 ^ 80 45-60 65 35

As a consequence, as retention time, peaks at about 15 minutes were observed for Compound 1 of the invention, about 30 minutes for Compound 2 and about 25 minutes for Compound 3.

Calibration curves were obtained using known amounts of the respective standard materials of the compounds of the invention. The calibration curves showed linearity.

It has been confirmed that a quantitative measurement is possible for the compounds of the invention by the HPLC conditions of the present invention. (TEST EXAMPLE 8)

Suppression effect of PGE2 production from MG-63 cells stimulated with IL-ßβ

For the compounds of the invention, the effect on suppression of PGE2 production caused by Interleukin (ILJ-β, which is an inflammatory stimulant material, has been investigated according to the method of International Patent Publication No. WO 03/70686.

As a consequence, all compounds obtained by the methods described in Examples 1 to 9 suppressed the production of PGE2 caused by IL-β, by 50% or more at 0.1 Μ. In addition, no cytotoxic effect on cells was observed for any of the test compounds at this concentration. Accordingly, the compounds of the invention are useful as inhibitory drugs against the production of inflammatory prostaglandin. (TEST EXAMPLE 9)

Prophylactic and therapeutic effect against mouse adjuvant arthritis

For the compounds of the invention, the suppressive effect against paw plant edema in rat adjuvant arthritis, which is a pathological model for chronic rheumatoid arthritis as one of the autoimmune diseases and also a chronic inflammatory disease, has been investigated according to the method of International Patent Publication No. WO 03/70686. The test compound was suspended in purified water containing 0.5% methylcellulose and was orally administered to test animals at a dose of 0.1 to 50 mg / 0.2 ml / kg.

As a consequence, both compounds obtained in Example 3 and Example 6 suppressed paw plant edema in rat adjuvant arthritis compared to the positive control group.

In addition, during the present assay, no mortality was observed in the test animals. Accordingly, the compounds of the invention are useful as prophylactic and / or therapeutic drugs for chronic rheumatoid arthritis and autoimmune diseases. (TEST EXAMPLE 10)

Observation by scanning electron microscope (SEM)

The crystals obtained in Example 3 or 4 of the present disclosure were observed by observation.

A measurement was made with the type A crystals of Compound 1 of the invention of Example 3 and, as a consequence, the SEM photograph shown in Fig. 11 was obtained.

A measurement was made with the type B crystals of Compound 1 of the invention of Example 4 and, as a consequence, the SEM photograph shown is shown in Fig. 12. However, these photographs are presented for reference purposes only, and the properties of any of the crystals of the present invention are not intended to be defined by, and need not be limited by, electron microscopy images.

Brief Description of Drawings

Fig. 1 is an X-ray diffraction spectrum of the crystals of Compound 2. In the diagram, the vertical axis indicates intensity (CPS) and the horizontal axis indicates 2Θ (°). 82

Fig. 2 is an X-ray diffraction spectrum of the crystals of Compound 3. In the diagram, the vertical axis indicates intensity (CPS) and the horizontal axis indicates 2Θ (°).

Fig. 3 is an X-ray diffraction pattern of the type A crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates intensity (CPS) and the horizontal axis indicates 2Θ (°).

Fig. 4 is a differential scanning calorimetric analysis of type A crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates mW and the horizontal axis indicates temperature (° C).

Fig. 5 is an infrared absorption spectrum of type A crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates transmittance (%) and the horizontal axis indicates cm-1.

Fig. 6 is an X-ray powder diffraction pattern of type B crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates intensity (CPS) and the horizontal axis indicates 2Θ (°).

Fig. 7 is a differential scanning calorimetric analysis of Type B crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates mW and the horizontal axis indicates temperature (° C).

Fig. 8 is an infrared absorption spectrum of type B crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates transmittance (%) and the horizontal axis indicates cm'1. 83

Fig. 9 shows a calibration curve for the differential scanning calorimetric analysis of type A crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates area (mJ) and the horizontal axis indicates weight (mg).

Fig. 10 shows a calibration curve for differential scanning calorimetric analysis of Type B crystals of Compound 1 of the invention. In the diagram, the vertical axis indicates area (mJ) and the horizontal axis indicates weight (mg).

Fig. 11 is an electron scanning (SEM) photograph, which is a photograph showing the crystalline form of the type A crystals of Compound 1 of the invention.

Fig. 12 is an electron scanning (SEM) photograph, which is a photograph showing the crystalline form of the B-type crystals of Compound 1 of the invention.

Lisbon, April 4, 2013 84

Claims (21)

A 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid B type crystal having at least one or more characteristic peaks at 2Θ selected from 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation . Type B crystal according to claim 1, wherein the crystal has characteristic peaks at 2Θ of 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation. Type B crystal according to claim 1 or 2, wherein the crystal has characteristic peaks at 2Θ of 8.6 ± 0.2 °, 9.8 ± 0.2 °, 14.4 ± 0.2 15.9 ± 0.2 °, 17.3 ± 0.2 °, 21.2 ± 0.2 °, 22.2 ± 0.2 °, 22.9 ± 0.2 °, 23.6 ± 0.2 ° and 28.4 ± 0.2 °, in an X-ray diffraction spectrum obtained using CuKa radiation. A type B crystal according to any of claims 1 to 3, wherein the crystal has an endothermic peak at about 203øC in differential scanning calorimetric analysis (heating rate: 10øC / min). A type B crystal according to any one of claims 1 to 4, wherein the crystal has infrared absorption bands at a wavelength of about 2939, 1720, 1 in an absorption spectrum of 1224, 1016 and 751 cm -1 obtained by the KBr disk method. A type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid having at least one or more peaks characteristic at 2Θ selected from 6.9 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° at a X-ray diffraction pattern obtained using CuKa radiation. Type A crystal according to claim 6, wherein the crystal has characteristic peaks at 2Θ of 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18, 2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation. Type A crystal according to claim 6 or 7, wherein the crystal has characteristic peaks at 2Θ of 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 20.0 ± 0.2 °, 20.7 ± 0.2 °, 22.9 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0 , 2 ° and 27.5 ± 0.2 ° in an X-ray diffraction spectrum obtained using CuKa radiation. A type crystal according to any of claims 6 to 8, wherein the crystal has an endothermic peak at about 182øC in differential scanning calorimetric analysis (heating rate: 10øC / min). Type A crystal according to any of claims 6 to 9, wherein it has infrared absorption bands at wavelengths of about 3361, 2938, 1712, 1204, 1011 and 2446 cm -1 in an absorption spectrum at the obtained by the KBr disk method. A pharmaceutical composition comprising 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid B type crystal according to any of claims 1 to 5, as an active ingredient, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable carrier is a dry product and the pharmaceutical composition is a dry preparation. A pharmaceutical composition according to claim 11 or 12, wherein the crystal purity of the type B crystal is at least 90% by weight or greater. A pharmaceutical composition comprising 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid A crystal according to any of claims 6 to 10, as an active ingredient, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable carrier is a dry product and the pharmaceutical composition is a dry preparation. A pharmaceutical composition according to claim 14 or 15, wherein the crystalline purity of the type A crystal is at least 90% by weight or greater. 3 A method of producing a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to of any of claims 1 to 5, the method comprising crystallizing 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid from of a solution having 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid dissolved in any one or two or more selected solvents of the group consisting of acetone, dichloromethane, methanol, ethyl acetate, mixed solution of methanol / acetic acid and acetonitrile. A method of producing a type B crystal according to any of claims 1 to 5, the method comprising adding an acid to a basic solution of 3- [3-amino-4- (indan-2-yloxy) 5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and thereafter adding B-type crystals of the compound as crystallization cores just before crystallization occurs by the addition of the acid, according to which they are formed 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid B type crystals. A method of producing a type B crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, from according to claim 18, wherein the basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is a alkaline hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid C1-4 alkyl ester. 4 A method of producing a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to of any of claims 6 to 10, the method comprising adding an acid to a basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5 -yl) phenyl] propionic acid to afford crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, and crystals. A method of producing a type A crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, according to claim 20, wherein the basic solution of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is a alkali hydrolyzate of a 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid C 1-4 alkyl ester. Lisbon, April 4, 2013 5